Effects of HMG-coA Reductase Pathway Inhibitors on GCAD

描述(申请人提供)：慢性排斥反应是心脏移植患者死亡的主要原因，但目前还没有有效的治疗方法。一种已经显示出希望的治疗方法是使用HMG-CoA还原酶抑制剂(他汀类)，但它们的作用机制尚不清楚。该提案描述了一项旨在阐明HMG-CoA还原酶途径抑制剂在预防小鼠心脏移植模型慢性排斥反应中的作用的研究项目。此外，这个项目将使人们更好地了解慢性排斥反应形成的途径。这将通过采用一种新的慢性排斥模型来实现，该模型依赖于生物发光成像。该项目有四个具体目标：(1)建立和验证FVB荧光素酶-GFP(β-肌动蛋白)到C57BL/6心脏移植慢性排斥反应的模型；(2)测定阿托伐他汀在该模型中降低慢性排斥反应程度的能力；(3)分析特定的HMG-CoA还原酶途径抑制剂在该模型中抑制慢性排斥反应的能力；以及(4)利用基因芯片检测抑制HMG-CoA还原酶途径对细胞内途径的影响。

DESCRIPTION (provided by applicant): Chronic rejection is the leading cause of death in heart transplant patients, yet, no effective treatment exists. One therapy that has shown promise is the use of HMG-CoA reductase inhibitors (statins), but the mechanism by which they operate remains unclear. This proposal describes a research project designed to delineate the role of HMG-CoA reductase pathway inhibitors in the prevention of chronic rejection in a murine cardiac transplant model. In addition, this project will lead to a greater understanding of the pathways affected in the formation of chronic rejection. This will be done by employing a novel model of chronic rejection which relies on bioluminescence imaging. The project has four specific aims: (1) the development and validation of the FVB Luciferase-GFP (beta-actin) to C57BL/6 cardiac transplant model of chronic rejection; (2) determination of the ability of atorvastatin to decrease the degree of chronic rejection in the model; (3) analysis of the ability of specific HMG-CoA reductase pathway inhibitors to suppress chronic rejection in this model; and (4) examination of the intracellular pathways affected by inhibition of the HMG- CoA reductase pathway using gene microarrays.